PROJECT SUMMARY Of all neurological diseases, the neuroinflammatory diseases are the most challenging. Many of these remain undiagnosed and are a major cause of morbidity and mortality. Several studies have shown that nearly a third of the patients on the neurology service at any tertiary care facility have undiagnosed neuroimmune diseases, many of whom have prolonged hospitalizations over several months and nearly a third of these patients die from the illness during this admission. These patients often undergo extensive investigations and multiple empirical therapies with poor results. They also bounce between physicians and major medical centers undergoing repeated investigations with no additional benefit. It is critically necessary that we develop a structured program to diagnose these patients, properly classify these disorders and develop a rational approach to treatment. Comprehensively investigating individual patients cannot only clarify their underlying diagnosis and lead to more directed therapies, but it can also fundamentally alter how we treat a neuroinflammatory disease more generally. For example, we discovered elevated PD-1 levels on lymphocytes in CSF of patients with progressive multifocal leukoencephalopathy which led to the development of a novel treatment for this otherwise fatal illness. Despite these efforts by individual laboratories, many cases still remain undiagnosed and untreated. This intramural and extramural highly collaborative proposal brings together for the first time physician-scientists and scientists across top academic and government institutions who have dedicated their careers to developing deep clinical phenotyping protocols for patients with idiopathic neuroinflammatory diseases as well as high-throughput and comprehensive tools for identifying microbial nucleic acid in the central nervous system, viral and autoantibody antibody profiling in the cerebrospinal fluid, immune cell profiling and T-cell antigen profiling. These investigations will not only lead to the identification of novel diseases in individual patients but also serve as a model for how neuroinflammatory diseases can be deciphered more widely.